Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide

• Sponsor: PharmaMar (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03117361
• Collaborator: (none)
• Enrollment: 10
• Locations: 13
• Arm: 1
• Actual Duration (Months): 14.7
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a multi-center, open-label, single arm, non-comparative phase II trial, designed to evaluate the efficacy of plitidepsin in combination with bortezomib and dexamethasone in patients with Multiple Myeloma (MM) double refractory to bortezomib and lenalidomide.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: plitidepsin; Drug: Bortezomib; Drug: Dexamethasone	Phase 2

Detailed Description

This is a multi-center, open-label, single arm, non-comparative phase II trial, designed to evaluate the efficacy of plitidepsin in combination with bortezomib and dexamethasone in patients with MM double refractory to bortezomib and lenalidomide.The primary endpoint will be overall response rate (ORR), including stringent complete response (sCR), complete response (CR), very good partial response (VGPR) and partial response (PR).

Approximately 64 evaluable patients will be needed for the evaluation of the primary endpoint, ORR.

An early futility analysis will be performed with the efficacy data collected from the first 20 evaluable patients. The futility analysis will commence once patient number 20 has completed two full treatment cycles. Patient recruitment will not be halted during the conduct of this futility analysis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Plitidepsin (Aplidin®) in Combination With Bortezomib and Dexamethasone in Multiple Myeloma Patients Double Refractory to Bortezomib and Lenalidomide
• Actual Study Start Date: May 8, 2017
• Actual Primary Completion Date: Jul 30, 2018
• Actual Study Completion Date: Jul 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental Plitidepsin + bortezomib + dexamethasone Plitidepsin will be administered as a 3-hour intravenous (i.v.) infusion on Day(D) 1 and 15 , every four weeks (q4wk) Bortezomib will be administered as a bolus subcutaneous (s.c.) injection on D 1, 4, 8 and 11,q4wk Dexamethasone will be taken orally on D1,8,15 and 22, q4wk	Drug: plitidepsin; Patients received plitidepsin as a 3-hour i.v. infusion at a dose of 5 mg/m2 on Days 1 and 15 every Four Weeks.; Drug: Bortezomib; BTZ as a 3-5 second bolus s.c. injection at a dose of 1.3 mg/m2 on Days 1, 4, 8 and 11 every four weeks; Drug: Dexamethasone; DXM orally at a dose of 40 mg/day on Days 1, 8, 15 and 22 every four weeks

Outcome Measures

Primary Outcome Measures

1. Overall Response [From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks]

   Partial response (PR): ≥50% reduction in serum M-protein and reduction of 24-hour urine M-protein by 90% or to <200 mg/24h Minimal response (MR): ≥25% but ≤49% reduction of serum M-protein and reduction of 24h urine M-protein 50-89%. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions Stable disease (SD): not meet the criteria for PR, MR or PD Primary analysis should have been done once a total of 64 patients have received plitidepsin+BTZ+DXM with one futility analysis planned after the inclusion of 20 evaluable patients that had completed two full treatment cycles. Only 10 patients were treatedand 8 evaluable for the primary endpoint (ORR according to IMWG criteria). As a result of slow patient accrual, the study was closed before reaching the target enrollment

2. Overall Response Rate [From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks]

   The primary endpoint was overall response rate (ORR) (including stringent complete response [sCR], complete response [CR], very good partial response [VGPR] and partial response [PR]), according to the IMWG response criteria.

Secondary Outcome Measures

1. Clinical Benefit Rate [From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks]

   Clinical benefit rate defined as minimal response or better

2. Disease Control Rate [From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks]

   Disease control rate defined as stable disease [SD] or better

3. Duration of Response [From the date of first documentation of response to the date of disease progression, up to 100 weeks]

   Duration of Response defined as the time, in months, from the date of first documentation of response to the date of disease progression. Response was assessed according to the IMWG classification response criteria.

4. Time to Progression [From the date of the first infusion to the date of documented PD or death due to PD, up to 100 weeks]

   Time to progression (TTP) was defined as the time, in months, from the date of the first infusion to the date of documented PD or death due to PD. TTP was to be censored on the date of the last tumor assessment or on the date of the first drug administration if there were no tumor assessments. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

5. Percentage of Participants With Progression Disease at 3 Months [From the date of the first infusion to the date of documented PD or death due to PD, up to 3 months]

   Progression disease was defined as documented PD or death due to PD Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

6. Percentage of Participants With Progression Disease at 6 Months [From the date of the first infusion to the date of documented PD or death due to PD, up to 6 months]

   Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions

7. Percentage of Participants With Progression Disease at 12 Months [From the date of the first infusion to the date of documented PD or death due to PD, up to 12 months]

   Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

8. Progression-free Survival [From the date of first drug administration to the date of documented PD, or death (of any cause), up to 100 weeks]

   Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

9. Percentage of Participants With Progression-free Survival at 3 Months [From the date of first drug administration to the date of documented PD, or death (of any cause), up to 3 months]

   Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

10. Percentage of Participants With Progression-free Survival at 6 Months [From the date of first drug administration to the date of documented PD, or death (of any cause), up to 6 months]

    Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

11. Percentage of Participants With Progression-free Survival at 12 Months [From the date of first drug administration to the date of documented PD, or death (of any cause), up to 12 months]

    Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

12. Event-free Survival [From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 100 weeks]

    Event-free survival (EFS) was defined as the time, in months, from the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death. The censoring rules defined above for PFS were used for EFS

13. Percentage of Participants With Event-free Survival at 3 Months [From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 3 months]

    Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. rogressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

14. Percentage of Participants With Event-free Survival at 6 Months [From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 6 months]

    Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

15. Percentage of Participants With Event-free Survival at 12 Months [From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 12 months]

    Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.

16. Overall Survival [From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 100 weeks]

    Overall survival (OS) was defined as the time, in months, from the date of first drug administration to the date of death (of any cause) or last patient contact (in this case, survival was to be censored on that date).

17. Percentage of Participants With Overall Survival at 6 Months [From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 6 months]

    Overall survival (OS) was defined as death of any cause.

18. Percentage of Participants With Overall Survival at 12 Months [From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 12 months]

    Overall survival (OS) was defined as death of any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients must give written informed consent (IC) in accordance with institutional and local guidelines.

2. Age ≥ 18 years.

3. Patients must have a confirmed diagnosis of MM according to the Durie and Salmon criteria.

4. Patients must have measurable disease defined as any of the following:

5. Serum M-protein ≥ 0.5 g/dL or ≥ 0.2 g/24-h urine light chain (UFLC) excretion.

6. In patients who lack measureable M-protein in serum or urine, i.e., serum M-protein < 0.5 g/dL and urine M-protein < 0.2 g/24 h, serum free light chain (SFLC) levels are most informative. SFLC levels can be used only if the baseline SFLC ratio is abnormal (<0.26 or >1.65), indicating clonality. In addition, the baseline SFLC level must be ≥10 mg/dl of the appropriate involved light chain isotype.

7. When applicable, measurable soft tissue plasmacytoma ≥ 2 cm, by either physical examination and/or applicable radiological evaluation (i.e., magnetic resonance imaging [MRI], computed tomography [CT]-scan).

8. Prior autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT) patients are allowed. Patients must not have acute/chronic graft-versus-host disease (GVHD) or be receiving immunosuppressive therapy at least 90 days before the onset of treatment with the trial drug(s).

9. Patients must have received previous treatment with bortezomib and lenalidomide and be refractory to both.

10. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2.

11. Recovery to grade ≤ 1 from any non-hematological adverse event (AE) derived from previous treatment (if present, alopecia and peripheral neuropathy must be grade <1).

12. Laboratory data:

13. Hemoglobin ≥ 8 g/dL.

14. Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (≥ 0.5 x 109/L if due to extensive bone marrow [BM] involvement by ≥ 50% of plasma cells in BM biopsy). Screening of ANC should be independent of granulocyte- and granulocyte/macrophage-colony stimulating factor (G-CSF and GM-CSF) support for at least one week and of pegylated G-CSF for at least two weeks.

15. Platelet count ≥ 50,000/mm3 (50.0 x 109/L) for patients in whom < 50% of the BM nucleated cells are plasma cells.

16. Platelet count ≥ 25,000/mm3 (25.0 x 109/L) for patients in whom ≥ 50% of BM nucleated cells are plasma cells.

17. Serum total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except when Gilbert syndrome is clearly documented and other liver function tests are within normal levels).

18. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x institutional ULN and alkaline phosphatase (AP) ≤ 2.5 x institutional ULN.

19. Creatinine clearance (CrCl) > 30 mL/min, measured or calculated according to Cockcroft and Gault's formula.

20. Albumin ≥ 2.5 g/dl.

21. Evidence of non-childbearing status for women of childbearing potential (WOCBP): WOCBP must have a negative serum or urine pregnancy test within seven days prior to enrolment and must agree to use a highly effective contraceptive measure throughout the trial and during six months after treatment discontinuation. Male patients enrolled in the study should also use contraceptive methods during and after treatment discontinuation.

22. Left ventricular ejection fraction (LVEF) ≥ 45%.

23. Patients must have a BM assessment within three weeks prior to enrolment.

Exclusion Criteria:

1. Previous treatment with plitidepsin.

2. Active or metastatic primary malignancy other than MM.

3. Serious concomitant systemic disorders that would compromise the safety of the patient or the patient's ability to complete the trial, including the following specific conditions:

4. Uncontrolled psychiatric illness or medical illness that the Investigator feels will compromise the patient's tolerance of the trial medication.

5. Significant non-neoplastic liver disease.

6. Uncontrolled endocrine diseases (i.e., requiring relevant changes in medication within the last month, or hospital admission within the last three months).

7. Uncontrolled systemic infection.

8. Acute infiltrative pulmonary and pericardial disease.

9. Other relevant cardiac conditions:

10. Symptomatic arrhythmia (excluding anemia-related grade ≤ 2 sinusal tachycardia) or any arrhythmia requiring ongoing treatment, and/or prolonged grade ≥ 2 QT-QTc; or presence of unstable atrial fibrillation (according to the National Cancer Institute Common Terminology Criteria for the Classification of Adverse Events [NCI-CTCAE] v4.0). Patients on treatment for stable atrial fibrillation are allowed, provided they do not meet any other cardiac or prohibited drug exclusion criterion.

11. History or presence of unstable angina, myocardial infarction, valvular heart disease, cardiac amyloidosis or congestive heart failure within the last 12 months.

12. Uncontrolled arterial hypertension (≥ 150/100 mmHg) despite optimal medical therapy.

13. Previous treatment with doxorubicin at cumulative doses of > 400 mg/m², or equivalent.

14. History of hypersensitivity reactions and/or intolerance to bortezomib, polyoxyl 35 castor oil, mannitol, boron or dexamethasone.

15. Myopathy or any clinical situation that causes significant and persistent elevation of creatine phosphokinase (CPK) (> 2.5 ULN) in two different determinations performed within one week of each other.

16. Grade ≥ 1 neuropathy (either bortezomib-related or not) according to NCI-CTCAE v4.0.

17. Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patients' participation in this trial.

18. Pregnant and/or lactating women.

19. Known active human immunodeficiency virus (HIV) infection (HIV testing is not required unless infection is clinically suspected).

20. Active hepatitis B or C virus (HBV or HCV) infection.

21. Treatment with any Investigational Medicinal Product (IMP) in the 30 days before inclusion in the trial.

22. Concomitant medications that include corticosteroids, chemotherapy (CT), or other therapy that is or may be active against myeloma. Concurrent corticosteroids are allowed as an equivalent to a prednisone dose of ≤ 10 mg daily, administered as an antiemetic or as premedication for blood products.

23. Wash-out periods after the end of the previous therapy:

24. Nitrosoureas must be discontinued six weeks prior to Cycle (C) 1, D1.

25. Thirty days for other CTs and 15 days for other biological agents prior to C1 D1.

26. Thirty days after the end of any prior radiation or radionuclide therapy (six weeks in the case of prior extensive external beam radiation, with more than 25% of BM distribution).

27. Plasma cell leukemia at the time of trial entry.

28. Disease-related symptomatic hypercalcemia despite optimal medical therapy.

29. Limitation of the patient's ability to comply with the treatment or follow-up protocol.

30. Contraindication to use steroids.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHRU de Lille - Hôpital Claude Huriez	Lille		France	59037
2	Institut Gustave Roussy	Villejuif		France	94800
3	Policlinico Vittorio Emanuele Hospital	Catania		Italy	95123
4	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola		Italy	47014
5	Azienda Ospedaliera Città della Salute e della Scienza di Torino	Torino		Italy	00126
6	Hospital Universitario Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
7	Clinica Universidad de Navarra	Pamplona	Navarra	Spain	31008
8	Institut Català d´Oncologia Girona	Girona		Spain	17007
9	Institut Català d´Oncologia L´Hospitalet	Hospitalet de Llobregat		Spain	08908
10	Hospital General Universitario J.M. Morales Meseguer	Murcia		Spain	30008
11	Hospital Universitario de Salamanca	Salamanca		Spain	37007
12	Complexo Hospitalario Universitario de Santiago	Santiago De Compostela		Spain	15706
13	Complejo Hospitalario Regional Virgen Del Rocio	Sevilla		Spain	41013

Sponsors and Collaborators

• PharmaMar

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Nov 10, 2015
• Statistical Analysis Plan - Dec 13, 2016

More Information

Publications

None provided.

• Responsible Party: PharmaMar
• ClinicalTrials.gov Identifier: NCT03117361
• Other Study ID Numbers: APL-B-022-15
• First Posted: Apr 17, 2017
• Last Update Posted: Dec 2, 2020
• Last Verified: Nov 1, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by PharmaMar: multiple myeloma; plitidepsin; Aplidin
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bortezomib

Study Results

Participant Flow

Recruitment Details	Patients participated between 15May2017 - 30Jul2018 (last follow-up cutoff date). The 1st dose/1st cycle was administered on 15May2017 and the last dose/last cycle on 23Jul2018. At cutoff date 10 patients had been included and treated with plitidepsin+BTZ+DXM and they were evaluable for safety. 8 of these were evaluable for the efficacy endpoint
Pre-assignment Detail	IC signed;Age≥18 years;confirmed diagnosis of MM,ECOG PS≤2;LVEF≥45%;negative pregnancy test

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Period Title: Overall Study
STARTED	10
COMPLETED	0
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	8 80%
>=65 years	2 20%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	5 50%
Male	5 50%
Race/Ethnicity, Customized (Count of Participants)
White	7 70%
Other	3 30%
Region of Enrollment (Count of Participants)
Italy	4 40%
France	3 30%
Spain	3 30%
ECOG PS (Count of Participants)
PS 0	5 50%
PS 1	4 40%
PS 2	1 10%
Multiple myeloma type at diagnosis (Count of Participants)
Secretory IgA	2 20%
Secretory IgG	4 40%
Secretory Kappa light-chain disease	2 20%
Secretory Lambda light-chain disease	2 20%
Durie-Salmon stage and subclassification at diagnosis (Count of Participants)
IIA	2 20%
IIIA	3 30%
IIIB	1 10%
Missing	4 40%
ISS stage at diagnosis (Count of Participants)
ISS I	1 10%
ISS II	1 10%
ISS III	4 40%
Not done	4 40%
R-ISS stage at study entry (Count of Participants)
Stage II	3 30%
Stage III	3 30%
Non available genetic results	4 40%
Cytogenetic at study entry (Count of Participants)
High risk	2 20%
Standard risk	4 40%
Non available genetic results	4 40%
Disease status with respect to last prior therapy (Count of Participants)
Primary Refractory	7 70%
Relapsed and refractory	3 30%
Best response to last prior anticancer therapy (Count of Participants)
PR	2 20%
MR	1 10%
SD	2 20%
PD	5 50%
Prior HSCT (Count of Participants)
Autologous	6 60%
Autologous and allogenic	2 20%
No	2 20%
Lines of prior chemotherapy (Count of Participants)
3 lines	1 10%
4 lines	2 20%
5 lines	4 40%
8 lines	2 20%
9 lines	1 10%
Weight (kg) [Median (Full Range) ]
Median (Full Range) [kg]	71.4
Height (cm) [Median (Full Range) ]
Median (Full Range) [cm]	167.1
Body surface area (m^2) [Median (Full Range) ]
Median (Full Range) [m^2]	1.8
Time from diagnosis to first plitidepsin infusion (months) [Median (Full Range) ]
Median (Full Range) [months]	70.7
Time from last progressive disease to first infusion (weeks) [Median (Full Range) ]
Median (Full Range) [weeks]	5.3
Lines of prior chemotherapy (Lines) [Median (Full Range) ]
Median (Full Range) [Lines]	5
Agents of prior chemotherapy (Agents) [Median (Full Range) ]
Median (Full Range) [Agents]	9
TTP to last anticancer therapy (months) [Median (Full Range) ]
Median (Full Range) [months]	3.4

Outcome Measures

1. Primary Outcome

Title	Overall Response
Description	Partial response (PR): ≥50% reduction in serum M-protein and reduction of 24-hour urine M-protein by 90% or to <200 mg/24h Minimal response (MR): ≥25% but ≤49% reduction of serum M-protein and reduction of 24h urine M-protein 50-89%. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions Stable disease (SD): not meet the criteria for PR, MR or PD Primary analysis should have been done once a total of 64 patients have received plitidepsin+BTZ+DXM with one futility analysis planned after the inclusion of 20 evaluable patients that had completed two full treatment cycles. Only 10 patients were treatedand 8 evaluable for the primary endpoint (ORR according to IMWG criteria). As a result of slow patient accrual, the study was closed before reaching the target enrollment
Time Frame	From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
PR	1 10%
MR	1 10%
SD	5 50%
PD	1 10%

2. Primary Outcome

Title	Overall Response Rate
Description	The primary endpoint was overall response rate (ORR) (including stringent complete response [sCR], complete response [CR], very good partial response [VGPR] and partial response [PR]), according to the IMWG response criteria.
Time Frame	From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	12.5 125%

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	Clinical benefit rate defined as minimal response or better
Time Frame	From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

4. Secondary Outcome

Title	Disease Control Rate
Description	Disease control rate defined as stable disease [SD] or better
Time Frame	From the date of first drug administration to the date of at least one disease assessment, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	87.5 875%

5. Secondary Outcome

Title	Duration of Response
Description	Duration of Response defined as the time, in months, from the date of first documentation of response to the date of disease progression. Response was assessed according to the IMWG classification response criteria.
Time Frame	From the date of first documentation of response to the date of disease progression, up to 100 weeks

Outcome Measure Data

Analysis Population Description

Only one patient achieved a partial response

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	1
Number [months]	9.2

6. Secondary Outcome

Title	Time to Progression
Description	Time to progression (TTP) was defined as the time, in months, from the date of the first infusion to the date of documented PD or death due to PD. TTP was to be censored on the date of the last tumor assessment or on the date of the first drug administration if there were no tumor assessments. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of the first infusion to the date of documented PD or death due to PD, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Median (95% Confidence Interval) [months]	2.7

7. Secondary Outcome

Title	Percentage of Participants With Progression Disease at 3 Months
Description	Progression disease was defined as documented PD or death due to PD Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of the first infusion to the date of documented PD or death due to PD, up to 3 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	37.5 375%

8. Secondary Outcome

Title	Percentage of Participants With Progression Disease at 6 Months
Description	Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions
Time Frame	From the date of the first infusion to the date of documented PD or death due to PD, up to 6 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

9. Secondary Outcome

Title	Percentage of Participants With Progression Disease at 12 Months
Description	Progression disease was defined as documented PD or death due to PD. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of the first infusion to the date of documented PD or death due to PD, up to 12 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

10. Secondary Outcome

Title	Progression-free Survival
Description	Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of documented PD, or death (of any cause), up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Median (95% Confidence Interval) [months]	2.7

11. Secondary Outcome

Title	Percentage of Participants With Progression-free Survival at 3 Months
Description	Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of documented PD, or death (of any cause), up to 3 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	37.5 375%

12. Secondary Outcome

Title	Percentage of Participants With Progression-free Survival at 6 Months
Description	Progression-free Survival was defined as documented PD, or death of any cause. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of documented PD, or death (of any cause), up to 6 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

13. Secondary Outcome

Title	Percentage of Participants With Progression-free Survival at 12 Months
Description	Progression-free survival (PFS) was defined as the time, in months, from the date of first drug administration to the date of documented PD, or death (of any cause). If any patient was lost to follow-up before PD or received another antitumor therapy, PFS was to be censored on the date of the last tumor assessment. If there were no tumor assessments, these parameters were to be censored on the date of the first drug administration Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of documented PD, or death (of any cause), up to 12 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

14. Secondary Outcome

Title	Event-free Survival
Description	Event-free survival (EFS) was defined as the time, in months, from the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death. The censoring rules defined above for PFS were used for EFS
Time Frame	From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Median (95% Confidence Interval) [months]	2.7

15. Secondary Outcome

Title	Percentage of Participants With Event-free Survival at 3 Months
Description	Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. rogressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 3 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	37.5 375%

16. Secondary Outcome

Title	Percentage of Participants With Event-free Survival at 6 Months
Description	Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 6 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

17. Secondary Outcome

Title	Percentage of Participants With Event-free Survival at 12 Months
Description	Event-free survival (EFS) was defined as the first drug-related event leading to treatment discontinuation, documented PD or death. Progressive disease (PD): 25% increase from the lowest response value in any of the following: serum M-protein, urine M-protein, BM plasma cell percentage, or difference in the kappa and lambda FLC. PD also diagnosed when an increase size or new bone lesions.
Time Frame	From the date of first drug administration to the date of onset of the first drug-related event leading to treatment discontinuation, documented PD or death, up to 12 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	25.0 250%

18. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS) was defined as the time, in months, from the date of first drug administration to the date of death (of any cause) or last patient contact (in this case, survival was to be censored on that date).
Time Frame	From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 100 weeks

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Median (95% Confidence Interval) [months]	NA

19. Secondary Outcome

Title	Percentage of Participants With Overall Survival at 6 Months
Description	Overall survival (OS) was defined as death of any cause.
Time Frame	From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 6 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	55.6 556%

20. Secondary Outcome

Title	Percentage of Participants With Overall Survival at 12 Months
Description	Overall survival (OS) was defined as death of any cause.
Time Frame	From the date of first drug administration to the date of death (of any cause) or last patient contact, up to 12 months

Outcome Measure Data

Analysis Population Description

1 died without any valid tumor assessment done 1 discontinued treatment-related AEs

Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
Measure Participants	8
Number (95% Confidence Interval) [percentage of participants]	55.6 556%

Adverse Events

Time Frame	From first infusion to 30 days after the last administration of trial drug and until their resolution, an average of 2 years
Arm/Group Title	Experimental
Arm/Group Description	Plitidepsin was to be administered as a 3-hour (h) intravenous (i.v.) infusion at a dose of 5 mg/m2, on Day (D) 1 and 15, every four weeks (q4wk); BTZ was to be administered as a subcutaneous (s.c.) injection at a dose of 1.3 mg/m2 on D1, 4, 8 and 11, q4wk and DXM was to be taken orally at a dose of 40 mg/day on D1, 8, 15 and 22, q4wk. A cycle was defined as 28 days, plus any additional days required for dosing delays due to any reason. Treatment cycles were repeated q4wk.
All Cause Mortality
	Experimental
	Affected / at Risk (%)	# Events
Total	3/10 (30%)
Serious Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	5/10 (50%)
Blood and lymphatic system disorders
Anaemia	1/10 (10%)	1
Thrombocytopenia	1/10 (10%)	1
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/10 (10%)	1
General disorders
Pyrexia	1/10 (10%)	1
Infections and infestations
Cellulitis	1/10 (10%)	2
Respiratory tract infection	1/10 (10%)	1
Metabolism and nutrition disorders
Hypercalcaemia	1/10 (10%)	1
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	1/10 (10%)	1
Nervous system disorders
Sciatica	1/10 (10%)	1
Renal and urinary disorders
Acute kidney injury	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	Experimental
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
Anaemia	6/10 (60%)	25
Neutropenia	3/10 (30%)	5
Thrombocytopenia	4/10 (40%)	35
Ear and labyrinth disorders
Vertigo	1/10 (10%)	1
Eye disorders
Cataract	1/10 (10%)	2
Gastrointestinal disorders
Constipation	2/10 (20%)	3
Diarrhoea	2/10 (20%)	7
Gastric disorder	1/10 (10%)	1
Gingival bleeding	1/10 (10%)	1
Mouth haemorrhage	1/10 (10%)	2
Nausea	5/10 (50%)	8
Vomiting	2/10 (20%)	2
General disorders
Asthenia/Fatigue	4/10 (40%)	22
Extravasation	1/10 (10%)	1
Malaise	1/10 (10%)	1
Oedema peripheral	1/10 (10%)	7
Peripheral swelling	1/10 (10%)	1
Pyrexia	4/10 (40%)	6
Infections and infestations
Folliculitis	1/10 (10%)	1
Gastroenteritis	1/10 (10%)	1
Herpes zoster	1/10 (10%)	2
Influenza	1/10 (10%)	1
Nasopharyngitis	1/10 (10%)	1
Respiratory tract infection	1/10 (10%)	2
Injury, poisoning and procedural complications
Overdose	1/10 (10%)	1
Investigations
Alanine aminotransferase increased	4/10 (40%)	12
Antithrombin III decreased	1/10 (10%)	1
Aspartate aminotransferase increased	2/10 (20%)	2
Blood cholesterol	1/10 (10%)	1
Blood creatine phosphokinase increased	1/10 (10%)	1
Blood creatinine increased	1/10 (10%)	1
Blood lactate dehydrogenase increased	1/10 (10%)	1
Neutrophil count decreased	1/10 (10%)	1
Weight decreased	2/10 (20%)	3
Metabolism and nutrition disorders
Decreased appetite	2/10 (20%)	3
Hypercalcaemia	1/10 (10%)	1
Hyperglycaemia	1/10 (10%)	1
Hyperuricaemia	2/10 (20%)	3
Hypocalcaemia	1/10 (10%)	2
Hypokalaemia	2/10 (20%)	4
Hypomagnesaemia	2/10 (20%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	1/10 (10%)	7
Back pain	1/10 (10%)	1
Muscular weakness	1/10 (10%)	19
Musculoskeletal chest pain	1/10 (10%)	2
Myalgia	2/10 (20%)	2
Nervous system disorders
Headache	1/10 (10%)	1
Neuropathy peripheral	1/10 (10%)	1
Peripheral sensory neuropathy	2/10 (20%)	14
Sciatica	1/10 (10%)	4
Seizure	1/10 (10%)	1
Psychiatric disorders
Depression	1/10 (10%)	1
Renal and urinary disorders
Renal failure	1/10 (10%)	1
Respiratory, thoracic and mediastinal disorders
Catarrh	1/10 (10%)	2
Cough	1/10 (10%)	2
Epistaxis	1/10 (10%)	1
Respiratory failure	1/10 (10%)	1
Rhinorrhoea	1/10 (10%)	1
Surgical and medical procedures
Intramedullary rod insertion	1/10 (10%)	1
Vascular disorders
Haematoma	1/10 (10%)	2
Hypertension	2/10 (20%)	3

Limitations/Caveats

On 29052018 the Sponsor closed the recruitment of the study due to the slow patient accrual. Besides the negative opinion of the EMA recommending the refusal of the marketing authorization for plitidepsin for MM reinforced the decision.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.